It has been recognized that, when heat is applied to areas of animal tissue containing both normal and malignant cells sufficient to raise the temperature of such areas to the range of 41.degree.-44.degree. C., a preferential destruction of the malignant cells occurs. (Normal animal tissue is destroyed at a temperature of about 48.degree. C.) Examinations of tumors subjected to such heat treatments utilizing light microscope and electron microscope techniques have revealed that the tumors undergo specific destruction with no substantial damage to adjacent normal cells such as fibroblasts and endothelial cells. The initial result of hyperthermia applied to solid in vivo tumors is the rapid increase of lysosomal enzyme activity in the cytoplasm of malignant cells with concomitant inhibition of respiratory metabolism. Significantly, a simultaneous depression of anaerobic glycolysis does not take place in the malignant cells, thereby promoting the accumulation of lactic acid first in the intracellular spaces and subsequently in the extracellular spaces. Inasmuch as most solid tumors exhibit slow exchange between intracellular fluid and blood, and this circumstance is particularly true in the central tumor regions, acidic conditions become predominant within the tumor during hyperthermia. This increase in acidity leads directly to enhanced lysosomal enzymatic activity (pH maxima 5-5.5). The nonmalignant cells surrounding the tumor sustain only minor and reversible damage. Both malignant and normal tissue demonstrate a rapid and marked inhibition of RNA synthesis which is subsequently followed by the partial inhibition of DNA and protein synthesis. A transitory effect on cell proliferation has also been observed. Nevertheless, those adverse effects are customarily eclipsed by the highly desirable rapid and pronounced lysosomal destruction occurring preferentially in the malignant cells. The biochemical lesion(s) affecting both RNA and DNA metabolism and the cells' ability to divide appear to be transient and are not believed to be the primary cause of hyperthermia-induced destruction. It has been postulated that a significant factor in normal cell survival resides in the anatomical location of those cells, i.e., the normal cells are located near the periphery of the tumor and are closely related to the blood vessels, thereby minimizing the buildup of acidity in their immediate environment. Hyperthermia has been found to interact synergistically with ionizing radiation treatment and chemotherapy, a factor which augments its clinical utility as an anticancer treatment modality.
The major obstacle impeding the widespread clinical utilization of hyperthermia in treating carcinomata has been the inability to deliver localized hyperthermia. Thus, early experimentation involving exposing an entire body to diathermy at temperatures of about 41.degree. C. had evidenced a temporary regression of tumors, but shortly after the treatment the tumors began to grow rapidly again.
Attempts have been made to localize heating in the tumor-containing area with a minimum deleterious effect upon adjacent normal tissue through the use of such means as electromagnetic fields, e.g., lasers and microwaves, and radio frequency (RF) induced magnetic fields. The latter has been the subject of several publications, for example: "Selective Inductive Heating of Lymph Nodes", Gilchrist et al., Annlas of Surgery, 146, No. 4, pages 596-606, September, 1957; "Controlled Radio-Frequency Generator for Production of Localized Heat in Intact Animal", Medal et al., American Medical Association Archives of Surgery, 79, pages 83-87, September, 1959; and "Selective Heating and Cooling of Tissue in Cancer Chemotherapy", Shingleton et al., Annals of Surgery, 156, No. 3, pages 408-416.
Those publications described the implantation of powdered magnetic materials, specifically a magnetic form of iron oxide statedly defined as Fe.sub.2 O.sub.3, into tissue. These particles became heated as a result of the coupling to the magnetic field through their dielectric and hysteresis loss. Those studies utilized magnetic fields at radio frequencies between about 0.12-2 megahertz.
Although initial experiments demonstrated that this method for localizing induction heating was operable in destroying metastases, two factors militated against this method being accepted as a useful modality for treating carcinomata. First, the magnetic form of iron oxide is insoluble in body fluids and in substantial concentrations may be toxic to and/or rejected by the body, and, second, the normal tissue surrounding the tumor became too hot during the heating operation and was subject to necrosis. This latter effect was due to dielectric heating, i.e., heating resulting from ionic conductivity of body tissue and fluids.
It has been recognized that more disparate heating between the suscepted region and the surrounding region would occur if the excitation field were of lower frequency. The heating of normal tissue takes place through dielectric heating which is a function of the field of frequency squared or even higher, depending upon the loss tangent, whereas magnetic hysteresis heating varies linearly with field frequency. Up to the present time, however, there has been no magnetic material with the necessary chemical, mechanical, and magnetic properties to be useful in contact with animal tissue while permitting the required heating to occur at reduced field frequencies.